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Proteolytic Regulation of Troponin T & Cardiac Function

肌钙蛋白 T 的蛋白水解调节

基本信息

批准号：
8918199
负责人：
Jian-Ping Jin
金额：
$ 5.95万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8918199
关键词：
ATP phosphohydrolase Actomyosin Adenosinetriphosphatase Acute Affect Alternative Splicing Animals Binding Binding Sites Biochemical Biochemistry C-terminal Calcium Calmodulin Calpain Cardiac Cardiac Muscle Contraction Cardiac Myocytes Cessation of life Chronic Complex Congestive Heart Failure Development Dose Excision Exercise Family Financial compensation Foundations Functional disorder Future Genes Health Heart Heart failure Immunoglobulin Variable Region Infarction Injury Ischemia Knowledge Lead Life Link Mechanics Microfilaments Modeling Modification Molecular Conformation Motor Mus Muscle Muscle Cells Myocardial Myocardial Contraction Myocardial Ischemia Myocardial dysfunction Myocardium Myofibrils Myosin ATPase Myosin Light Chains N-terminal Nature Phase Phenotype Physiologic intraventricular pressure Physiological Plant Roots Post-Translational Protein Processing Post-Translational Regulation Preparation Prevention approach Production Protein Binding Protein Subunits Proteolysis Pump Rattus Regulation Regulation of Proteolysis Reperfusion Injury Reperfusion Therapy Reporting Research Project Grants Role Skin Stress Stretching Striated Muscles Structure Structure-Activity Relationship System Testing Thin Filament Time Transgenic Mice Transgenic Organisms Translating Tropomyosin Troponin Troponin C Troponin I Troponin T Variant Ventricular Work base cardiogenesis clinical application connectin coping functional loss genetic regulatory protein heart function improved in vivo novel postnatal pressure protein complex receptor reconstitution research study response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Cardiac muscle contraction is regulated by Ca2+ through the troponin complex that consists of three protein subunits: troponin C, troponin I, and troponin T (TnT). This research project investigates the role of a novel posttranslational modification of cardiac TnT (cTnT) in myocardial adaptation to energetic crisis. We recently reported a restricted N-terminal proteolysis of cTnT in myocardial ischemia-reperfusion (Zhang et al., Biochemistry 45:11681-94, 2006) and pressure overload (Feng et al., J. Physiol. 586:3537-50, 2008). This modification selectively removes the N-terminal variable region of cTnT but keeps the conserved middle and C-terminal regions intact. Initial studies in transgenic mouse hearts showed that the N-terminal truncated cTnT (cTnT-ND) remains functional in the myofilaments and alters myocardial contractility. This finding has lead to a hypothesis that the proteolytic removal of the N-terminal variable region of cTnT produces a functional state in cardiac muscle thin filaments as acute adaptation to energetic crisis. To test this hypothesis and understand the physiological and pathophysiological significance of cTnT- ND, three Specific Aims are proposed in this research project: Aim I will characterize the effects of the selective deletion of the N-terminal variable region on the function of cTnT. We will examine the interactions of cTnT-ND with other thin filament regulatory proteins and its functional impacts on the Ca2+ activation of myofibril ATPase and the contractility of cardiac muscle. Aim II will study the role of N-terminal truncated cTnT in compensating cardiac function and providing myocardial protection against ischemia-reperfusion injury. The acute and chronic effects of cTnT-ND on heart function and its role in overcoming energetic crisis will be investigated in ex vivo working hearts and in vivo. Aim III will investigate the role of mechanical stretch of the cardiac muscle in inducing the restricted proteolytic cleavage of cTnT N-terminal segment in order to understand the mechanisms that regulates this posttranslational regulation. Using integrated experimental systems, this study will gain new knowledge for the structure-function relationships of TnT and lay a foundation for future development of new treatment of ischemic heart disease and heart failure.

描述（由申请人提供）：